8-24490886-C-G

Variant names:

• chr8-24490886-C-G
• NM_003817.4:c.1354C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003817.4(ADAM7):​c.1354C>G​(p.Gln452Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM7 NM_003817.4 missense, splice_region
• Scores: Splicing: ADA: 0.9425
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

ADAM7 (HGNC:214): (ADAM metallopeptidase domain 7) This gene encodes a member of the ADAMs family of zinc proteases. These transmembrane proteins play roles in multiple processes including cell signaling, adhesion and migration. The encoded protein lacks protease activity and may play roles in protein-protein interactions and cell adhesion processes including sperm-egg fusion. Mutations in this gene may be involved in the progression of melanoma. [provided by RefSeq, Oct 2011]

ADAM7-AS2 (HGNC:56153): (ADAM7 antisense RNA 2)

ADAM7-AS1 (HGNC:56152): (ADAM7, ADAMDEC1 and ADAM28 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM7	NM_003817.4	c.1354C>G	p.Gln452Glu	missense_variant, splice_region_variant	Exon 13 of 22	ENST00000175238.10	NP_003808.2
ADAM7-AS1	NR_125808.1	n.79+57654G>C		intron_variant	Intron 1 of 5
ADAM7-AS2	NR_125809.1	n.748-380G>C		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM7	ENST00000175238.10	c.1354C>G	p.Gln452Glu	missense_variant, splice_region_variant	Exon 13 of 22	1	NM_003817.4	ENSP00000175238.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1354C>G (p.Q452E) alteration is located in exon 13 (coding exon 13) of the ADAM7 gene. This alteration results from a C to G substitution at nucleotide position 1354, causing the glutamine (Q) at amino acid position 452 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.91	P;.;P
Vest4		0.49
MutPred		0.63		Gain of ubiquitination at K454 (P = 0.0469);Gain of ubiquitination at K454 (P = 0.0469);.;
MVP		0.44
MPC		0.24
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.44
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-24348399;